The present invention relates to the use of camptothecin derivatives, without entailing any gastrointestinal intolerance side effects, or with reduced gastrointestinal side effects. The present invention also relates to the use of sodium chloride solutions to reduce the gastrointestinal side effects entailed by the administration of camptothecin derivatives.
It is known that the administration of camptothecin derivatives causes many side effects. In particular in the gastrointestinal tract, they most commonly cause very serious vomiting and diarrhoea which can lead to interruption of the treatment.
European patent EP 137145 describes camptothecin derivatives of general formula: 
in which, in particular, R1 is hydrogen, halogen or alkyl, X is a chlorine atom or NR2R3 in which R2 and R3, which may be identical or different, can represent a hydrogen atom, an optionally substituted alkyl radical, a carbocycle or a heterocycle which are optionally substituted, or alkyl radicals (optionally substituted) forming, with the nitrogen atom to which they are attached, a heterocycle optionally containing another hetero atom chosen from O, S and/or NR4, R4 being a hydrogen atom or an alkyl radical, and in which the Xxe2x80x94COxe2x80x94Oxe2x80x94 group is located in positions 9, 10 or 11 on ring A. These camptothecin derivatives are anticancer agents which inhibit topoisomerase I, among which irinotecan, for which Xxe2x80x94COxe2x80x94Oxe2x80x94 is [4-(1-piperidino)-1-piperidino]carbonyloxy, is an active principle which is particularly effective on solid tumours and especially colorectal cancer.
Patent application EP 74256 also describes other camptothecin derivatives which are also mentioned as anticancer agents, in particular derivatives which have a structure similar to the structure given above and in which Xxe2x80x94COxe2x80x94Oxe2x80x94 is replaced with a radical xe2x80x94Xxe2x80x2Rxe2x80x2 for which Xxe2x80x2 is O or S, and Rxe2x80x2 is a hydrogen atom or an alkyl or acyl radical. Other camptothecin derivatives have also been described, for example, in patents or patent applications P 56692, EP 88642, EP 296612, EP 321122, EP 325247, EP 540099, EP 737686, WO 9003169, WO 9637496, WO 9638146, WO 9638449, WO 9700876, U.S. Pat. No. 7104894, JP 57 116015, JP 57 116074, JP 59 005188, JP 60 019790, JP 01 249777, JP 01246287, JP 91/12070, or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diegoxe2x80x9412-16 April), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PE-55 (Seoulxe2x80x9427 July-1 August).
Camptothecin derivatives are conventionally administered by injection, more particularly intravenously in the form of a sterile solution or of an emulsion. Camptothecin derivatives can also be administered orally, in the form of solid or liquid compositions.
Camptothecin derivatives can also be administered in combination with other anticancer agents, such as for example cisplatin, oxaliplatin, Tomudexo(copyright) (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-theonyl-L-glutamic acid)), Taxotere(copyright) (docetaxel), 5-fluorouracyl and thymidilate synthase inhibitors.
Unfortunately, among the clinical side effects linked to treatment with camptothecin derivatives, the onset of diarrhoea (of grade 3 or 4), of cholinergic syndrome, of nausea or vomiting is especially noted. In particular, in 38% of patients, severe diarrhoea is observed, which can endanger the life of the patients as a result of dehydration and/or associated infection.
Many strategies have been implemented in order to combat intestinal toxicity due to the administration of the active principle and to reduce it, but these have proved unsuccessful hitherto. The result of this is that camptothecin derivatives can only be used by very experienced oncologists and only for certain categories of patients who can tolerate them.
It has now been found, and it is this which forms the subject of the present invention, that protection against the gastrointestinal lesions induced by treatment with camptothecin derivatives can be obtained by the administration of a sodium chloride solution. The protection results in the reduction or even the specific elimination of the gastrointestinal side effects, without the systemic exposure to the active principle or the antitumour activity being reduced.